The goal of this program project is to understand the relationship between the latent state of the highly neurotropic varicella zoster virus (VZV) in human ganglia and the development of acute and chronic neurologic disease produced by virus reactivation. The program project contains an administrative core, a scientific core and 3 scientific projects. Primary infection by varicella zoster virus (VZV) usually causes varicella (chickenpox), after which virus becomes latent in human ganglionic neurons along the entire neuraxis. With aging, a declining cell-mediated immunity to VZV leads to virus reactivation, manifesting as herpes zoster (shingles) characterized by pain and rash restricted to 1-3 dermatomes. The incidence and severity of zoster is also high in transplant recipients and patients with cancer or AIDS. Zoster is frequently complicated by chronic pain (postherpetic neuralgia), as well as paralysis, blindness and stroke. Currently, ~1,000,000 Americans develop zoster annually. Oka VZV vaccine reduces the incidence of zoster by 50%, but even if every American over age 60 was vaccinated, >500,000 cases of zoster would still occur every year. This program project is focused exclusively on the molecular pathogenesis of primary VZV infection, latency and reactivation. Project 1 studies inhibition of apoptosis by both viral and cellular proteins during VZV infection of neurons that results in neuronal survival and viral latency. Project 2 studies molecular mechanisms of VZV latency and reactivation in ganglia, focusing on VZV IE63, the protein product of the most prevalent and abundant transcript identified in latently infected human ganglia, and whose translocation from the cytoplasm to the nucleus may result in altered IE63 function and induction of virus reactivation. Project 3 studies the immunobiology of varicella in an animal model, focusing on identification of host cell types and their role in transport and establishment of varicella infection in skin and ganglia during primary infection and cytokine expression and virus-specific T cells in varicella reactivation. A comprehensive knowledge of the physical state of latent and reactivated VZV and simian varicella virus (SVV) will provide the rational underpinning for strategies to prevent the cascade of events leading to human VZV reactivation, a cause of serious neurologic disease, particularly in the rapidly increasing elderly and immunocompromised populations. This proposal melds the skills and strategies of investigators with expertise in clinical neurology, virology, molecular and cell biology and clinical investigation.